Process for preparing ethers of 1alpha-hydroxy-3-keto-5alpha-steroids and intermediates therein



United States Patent Int. Cl. C07c 167/3 0, 169/34, 169/20 U.S. Cl.260-397.45 17 Claims ABSTRACT OF THE DISCLOSURE Ethers of1a-hydroxy-3-keto-5a-steroids are prepared by treating a corresponding A-3-keto-5ousteroid with an alkyl orthoformate and an alcohol. Theprocess occurs through new tri-ethers of 1a,3,3-trihydroxy-5a-steroidswhich are also useful as intermediates for the preparation of enolethers of A -3-keto-5a-steroids.

BACKGROUND OF THE INVENTION This invention relates to a process for thepreparation of ethers of 1a-hydroxy-3-keto-5a-steroids and to newtriethers of 111,3,3-trihydroxy-a-steroids useful as intermedi' ates insaid process.

It is known (German Patent 1,222,496) that lot-alkoxy-3-keto-5a-androstanes may be prepared from A -3-keto- Sa-androStenes bydirect addition of an alkanol to the double bond in l-position, underparticular reaction conditions. According to the aforesaid patent,'theaddition of alcohol occurs at very low temperatures around 40 to 20 C.,whereby long reaction times up to 96 hours are required to causeformation of the lot-alkoxy derivative. Moreover, since the reactionmust be effected in the presence of a large amount of alcohol (about -50times higher than the starting steroid), a simultaneous alcoholysis ofesters groups contained in the steroid molecule is frequently observed.Furthermore the reaction is hardly appliable to alcohols other thanmethanol owing to the poor reactivity of such alcohols.

Therefore the method of the prior art does not permit to obtainla-alkoxy-steroids in good yield with relatively short reaction timesand without concomitant side reactions.

SUMMARY OF THE INVENTION It has now been found that by subjecting a A-3-keto- Six-steroid to the concurrent action of an orthoformate and ofan alcohol at moderate temperature and in the presence of an acidcatalyst, a tri-ether of a 1oz,3,3-tlihydroxy-5u-steroid is rapidlyformed, which can be quantitatively converted under mild acidichydrolytic conditions to the corresponding ether of a 1a-hydroxy-3-keto-Son-SteIOid. The present invention thus provides in one of its aspects ageneral process for the preparation of ethers of1a-hydroxy-3-keto-5a-steroids which needs a very short reaction time andavoids the lowe temperatures required by the above German patent.

Furthermore the invention provides, in another of its aspects, a seriesof new tri-ethers of 1a,3,3-trihydroxy-5usteroids, particularly of theandrostane and pregnane series which, besides being valuableintermediates in the process of this invention, are also useful asintermediates in the preparation of the enol ethers of the A-3-keto5asteroids.

3,475,467 Patented Oct. 28, 1969 DETAILED DESCRIPTION OF THE INVENTIONThe process of this invention and the intermediates therein arerepresented by the following reaction sequence R0 no ROH R0 11+ (0R) H-Ca O RO/ E 0 I II III in which R is a lower hydrocarbon radical. The termlower hydrocarbon radical is intended to mean a lower, saturated orunsaturated, aliphatic radical containing from 1 to 6 carbon atoms suchas methyl, ethyl, propyl, allyl, propargyl, butyl, pentyl and theirbranched isomers, or a lower cycloaliphatic radical, particularlycyclopentyl. Preferred lower hydrocarbon radicals are methyl, ethyl,propyl, alyl and propargyl; the methyl radical being particularlypreferred.

The process of this invention comprises the step of reacting a A-3-keto-5a-steroid having at the ring A the structure I with an alcoholof formula ROH and an orthoformate of formula H-C(OR) in which R has theabove stated meaning under anhydrous conditions at a temperature below60 C. in the presence of an acid catalyst.

The reaction may be carried out in an ether or hydrocarbon solvent, suchas diethyl ether, tetrahydrofurane, dioxane, benzene, hexane, isooctaneand like as well as in halogenated hydrocarbons such as methylenechloride, chloroform or carbon tetrachloride.

Suitable acid catalysts are the aromatic sulfonic acids such as toluene,benzene and naphthalene sulfonic acids, salts or organic bases withstrong acids, such as pyridine hydrochloride or pyridine tosylate aswell as Lewis acids. Preferred acid catalyst is p-toluene sulfonic acid.

The mixture is maintained at a temperature below 60 C. for a period fromabout 30 minutes to about 4 hours, preferably under stirring; generallyafter an hour at room temperature the reaction can be considered to beover. At the end of the reaction by neutralizing the mixture with a fewdrops of a base, particularly pyridine, there is obtained an ether of al0:,3,3-trihydroxy-5a-steroid having at the ring A the structure II,which can be isolated according to conventional methods, for example byevaporation of the solvent and recrystallization of the residue or bydirect precipitation with water. Sometimes the precipitation may befavoured by letting the mixture to stand in an ice-box for a short time.

By subjecting the intermediate tri-ether thus obtained to hydrolysisunder mild acidic conditions, for example by treatment with diluteoxalic acid at room temperature for a short time, there is obtained withexcellent yield a corresponding ether of a 10:. hydroxy 3 keto 5asteroidhaving at the ring A the structure III above.

The process of this invention for the preparation of ethers of 1mhydroxy 3 keto 5oz steroids may be also carried out without isolatingthe intermediate triether of Formula II. For this purpose the reactionmixture, resulting from the treatment of the A 3 keto- 50c steroid withthe orthoformate and alcohol as said above and containing the tri-etherof Formula II, is directly worked under aqueous acidic conditions, forexample by adding thereto a few drops of water or of a dilute acid. Theethers of the la hydroxy 3 keto- 50c steroids III are so obtained by aone-step procedure.

In carrying out the process of the present invention it is necessary tobear in mind that both the alcohol and the orthoformate participate inthe reaction. Therefore they should have the same hydrocarbon radical inorder to obtain a single reaction product.

It may occur, however, that particular orthoformates are not promptlyavailable, for example when typical alcohols such as butyl or pentylalcohols are involved in the reaction. In this case one can employ asreaction components the easily available ethyl orthoformate togetherwith the desired alcohol. In the course of the process a main productforms consisting of .a triether of a 111,3,3 trihydroxy 50c steroid (ora corresponding ether of a la hydroxy 3 keto c: steroid according to theworking conditions) in which the ether radical is that of the alcoholemployed and a by-product consisting of the corresponding 1a,3,3 triethoxy 5a steroid (or la ethoxy 3 keto 5a steroid). The two products soobtained can be separated from each other for example by fractionalcrystallization or by chromatography. The amount of the two productsdepends on the nature and the proportions of the reacting ethylorthoformate and alcohol; however only one product can be practicallyobtained if the chosen alcohol is employed in excess over the ethylorthoformate.

It will be up to those skilled in the art to select everytime the moresuitable reaction conditions to obtain the best yield of the finalproduct; it is however necessary to point out that methanol and methylorthoformate are highly reactive, so that it is advisable to limit theiruse to the preparation of the la methoxy derivatives.

The process of this invention is quite general and may be applied to anyA 3 keto 5a steroid of the androstane, pregane, cholestane andsapogenine series. Possible substituents present in thecyclopentanepolyhydrophenanthrene nucleus, such as free, etherified oresterified hydroxy groups, sterically hindered keto groups, halogens,methyl or methylene groups in one or more of the 6, 7, 8, 9, 11, 12 or16 positions do not interfere with the formation of the ethers of thelot-hydroxy 3 keto 5a steroids. Other possible double bonds present atrings C and D do not alfect in any Way the process of the invention. Ifsome sterically unhindered keto groups are present in the molecule ofthe starting compound, they react in the first step of the process togive the corresponding ketal. However if the reaction mixture is thenworked under aqueous acidic conditions the starting keto groups arequantitatively restored.

Preferred tri ethers of 1a,3,3 trihydroxy 5asteroids obtained asintermediates according to the process of this invention, are those ofthe androstane and pregnane series represented by the followingformulas:

wherein R is a lower hydrocarbon radical as hereinabove defined, Yrepresents hydrogen, a ketonic oxygen or a 3 hydroxy group, X representshydrogen or fluorine, T is xCH [S -CH or 01-02, Z represents hydrogen oran acyl group derived from a carboxylic acid containing up to 9 carbonatoms and R is hydrogen or lower alkyl and in which X is fluorine onlywhen Y is fi-hydroxy.

The acyl groups derived from carboxylic acids containing up to 9 carbonatoms include saturated and unsaturated aliphatic acyl, benzoyl,substituted benzoyl, arylaliphatic acyl, cycloaliphatic acyl andcycloalkyl aliphatic acyl. Representative esters are the acetate,propionate, trimethylacetate, butyrate, isobutyrate,

valerate, caproate, oenanthate, benzoate, phenylpropionate,cyclopentylpropionate and cyclohexylacetate.

These compounds are particularly useful, because they can be easilypyrolyzed to corresponding enol ethers of the corresponding A 3 keto 5asteroids disclosed and claimed in our copending application Ser. No.640,- 419, filed May 22,1967.

The following examples illustrate the invention.

EXAMPLE 1 A mixture of 7.68 g. of 17fl-acetoxy-A -5u-androsten- 3-one,15 cc. of absolute methanol, 5 cc. of methyl orthoformate and 70 mg. ofp-toluenesulfonic acid is maintained under stirring at room temperaturefor about an hour and after addition of few drops of pyridine is kept inice-box for a further hour. The crystalline precipitate is filtered and4.12 g. of 1a,3,3-trimethoxy-l7fiacetoxy-5a-androstane are obtained.M.P. l0l-l03 C. (dec.); [a] =|30 (dioxane, c.=0.5%). The mother watermaintained in ice-box for a further hour, give other 1.77 g. of1a,3,3-trimethoxy-l7 8-acetoxy-5a androstane M.P. 102 C.

500 mg. of this product in 25 cc. of methanol are treated with 500 mg.of oxalic acid dissolved in 5 cc. of water. The mixture is let to standat room temperature for an hour, then is neutralized with sodiumbicarbonate and precipitated with water. The precipitate is filtered andcrystallized from methanol to give the1u-methoxy-17fiacetoxy-Sa-androstan-3-one; M.P. l-l97 C.,

]n =i+ (dioxane, c.=0.5%

EXAMPLE 2 A mixture of 5 g. of 17/3-acetoxy-A -5u-androsten-3- one, 6cc. of ethyl orthoformate, 15 cc. of absolute ethanol and g. ofp-toluenesulfonic acid is maintained under stirring at room temperaturefor an hour, then is treated with a few drops of pyridine andconcentrated under vacuum. The residue, taken up with methanol, givesthe 1a,3,3-triethoxy-17,8-acetoxy-5 a-androstaner, M.P. 6570 C., [a]=i+45.5 (dioxane, c.=0.5%).

By hydrolyzing this product as in Example 1, 10t-thOXy-17/3-acetoxy-5a-androstan-3-one is obtained.

EXAMPLE 3 A mixture of 1 g. of 17,8-acetoxy-A -5ot-androsten-3- one, 0.7g. of ethyl orthoformate, 2 cc. of allyl alcohol and 10 mg. ofp-toluenesulfonic acid is stirred at room temperature for about an hourthen is treated with a few drops of pyridine and concentrated undervacuum. The residue, taken up with methanol gives thela,3,3-triallyloxy-17fl-acetoxy-5a-androstane.

IR. spectrum maxima: 1740, 1650, 1250, 1185, 1175, 1115, 1092,1030, 920,850 and 735 cm.

By hydrolyzing this product as in Example 1.laallyloxy-l7/3-acetoxy-5u-androstan-3-one is obtained.

EXAMPLE 4 A mixture of 1 g. of l7fi-acetoxy-A -5a-androsten-3- one, 0.5cc. of ethyl orthoformate, 1 cc. of propargyl alcohol and 10 mg. ofp-toluenesulfonic acid is treated as described in Example 3 to give thela,3,3-tripropargyloxy-17,3-acetoxy-5inc-androstane.

IR. spectrum maxima: 3250, 2120, 1730, 1250, 1180, 1050, 1025, 925, 840and 755 cm.-

By hydrolyzing this product as in Example 1.1apropargyloxy-l7p-acetoxy-5ot-androstan-3-one is obtained.

EXAMPLE 5 A solution of 1 g. of -acetoxy-A -5a-androsten-3- one, 0.7 g.of ethyl orthoformate, 2 cc. of cyclopentanol and 10 mg. of pyridinetosylate in 30 cc. of anhydrous tetrahydrofurane is maintained understirring at room temperature for about an hour, then is treated asdescribed TABLE II Example Tri-ether of the 1a,3,3-tri- Ether of thela-hydroxy-S- No. Startmg material hydroxy-a-steroid keto-5a-steroid 26166-111ethyl-Zl-valeroxy-A -m-pregne-l1B,1a,3,3-trlrnethoxy-16B-methyl-21-valeroxy-1a-methoxy-1(id-n1ethyl-2l-valeroxy-5a-preg 17a-diol-3,20-dione.5a-pregnane-l13,17a-diol-20-one. nane-l1fi,17a-dio1-3,20-dione. 2716/8-methyl-21-(B-phenyl)-pr0pionoxy-A -5a-1a,3,3-trimethoxy-16B-methyl-2l-(B-phenyl)-la-methoxy-lGfl-methyl-Zl-(fl-phenyl)pro- 28lfioz-methyl-Zl-(fi-cyclopentyl) propionoxy- A-Sa-pregnene-IIB,17a-diol-3,2Odione.

propionoxy-Sa-pregnane-11fi,17a-diol-20- one.la,3,3-trimethoxy-lGa-methyl-Zl-(fl-cyclopentyl)propionoxy-fioz-pregnane-l16,170:-

EXAMPLE 31 A mixture of 5 g. of A -5a-andr0stene-3,17-dione, 6 cc. ofmethyl orthoformate, 15 cc. of absolute methanol and 125 mg. ofp-toluenesulfonic acid is stirred at room temperature for an hour, thentreated with a few drops of pyridine. The solvent is evaporated undervacuum and the residue crystallized from methanol to obtain the1a,3,3,17,17-pentamethoxy-5a-androstane, M.P. 162165 C.; [u] =+46, 5(dioxane, c.=0.5%). The product thus obtained is dissolved in littlemethanol and treated with a few drops of dilute hydrochloric acid. Afterminutes at room temperature the solution is neutralized with sodiumbicarbonate and precipitated with water. The precipitate is filtered andcrystallized from methanol to give lu-methoxy-5a-androstane 3,17 dione,M.P. 177- 179 C., [a] =-I125 (dioxane, c.=0.5%).

EXAMPLE 32 To a suspension of 1 g. of 17,8-acetoxy-A -5a-androsten-3-one in 2 cc. of methanol and 0.75 cc. of methyl orthoformate there areadded 7 mg. of p-toluene-sulfonic acid and the resulting solution isleft to stand at room temperature for 30 minutes. Upon addition understirring of few drops of water a crystallin precipitate separates giving0.84 g. of 1a-methoxy-l7B-acetoxy-5a-androstan-3-one; M.P. 195-197 C.,[a] =-|43 (dioxane, c.=0.5%).

The same product is obtained by employing ethyl orthoformate in lieu ofmethyl orthoformate.

In an analogous manner 1a-methoxy-5a-androstan-175- ol-3-one isobtained; M.P. 204-207 C.; [u] =+48 (dioxane, c.=0.5%).

EXAMPLE 33 By operating as in Example 32, by treating the 17pacetoxy-A-5a-androsten-3-one with ethyl orthoformate and ethanol in the presenceof p-toluene-sulfonic acid, the 1a-ethoxy-178-acetoxy-5a-androstan-3-one is obtained; M.P. 167-169 C.; [a] =+4l.5(dioxane, c.=0.5%). Yield in crystalline product: 40%.

EXAMPLE 34 A mixture of 1 g. of 17fi-acetoxy-A -5a-androsten-3- one, 0.7cc. of ethyl orthoformate, 2 cc. of allyl alcohol and 10 mg. ofp-toluenesulfonic acid is stirred at room temperature, for an hour thentreated with a few drops of water. The1a-allyloxy-17fi-acetoxy-5a-androstan-3- one is so obtained; M.P. 134137C.; [a] =+48 (dioxane, c=0.5%

In an analogous manner the1a-propargyloxy-flfi-acetoxy-5u-androstan-3-one is obtained; M.P. 187190C.; [a] =+42 (dioxane, c.=0.5%).

EXAMPLE 35 A mixture of 5 g. of 17/3-acetoxy-A -Sa-androsten-2- one, 6cc. of methyl orthoformate, 10 cc. of ethanol and 125 mg. ofp-toluenesulfonic acid is stirred at room temperature for an hour. Afteraddition of some drops of water the obtained precipitate is filtered andcrystallized from ether-petroleum ether to givela-methoxy-flp-acetoxy-5u-androstan-3-one, identical to the product ofExample 32.

The mother water is concentrated under vacuum and the residue, byfractional crystallization from methanol, givesla-ethoxy-l7fi-acetoxy-5a-androstan-3-one identical to the product ofExample 33.

EMMPLE 36 A mixture of 1 g. of A -5a-androsten-17/8-ol-3-one, 0.75 cc.of ethyl orthoformate, 2 cc. of ethanol and 7 mg. of p-toluenesulfonicacid is maintained under stirring for an hour at room temperature. Afteraddition of some drops of Water, there is obtained in about 50% yieldthe la-ethoxy-5a-androstan-17,8-ol-3-one, melting at 142-144" C.; [a]=-|42.5 (dioxane, c.=0.5%).

I.R. spectrum maxima at 3600, 1707, 1165, 1105, 1060 and 875 CHI-1.

We claim:

1. In a process for the preparation of ethers ofla-hydroxy-3-keto-5a-steroids, the step which comprises reacting a A-3-keto-5a-steroid having at the ring A the structure:

with an alcohol of formula ROH, in which R is a lower hydrocarbonradical and an orthoformate of formula HC(OR) in which R is ashereinabove defined under anhydrous conditions at a temperature below 60C. in the presence of an acid catalyst to obtain a tri-ether of a1,3,3-trihydroxy-5a-steroid having at the ring A the structure:

in which R is as hereinbefore defined.

2. A process as claimed in claim 1, in which the alcohol is methanol andthe orthoformate is methyl orthoformate.

3. A process as claimed in claim 1, in which the reaction is carried outat about room temperature.

4. A process as claimed in claim 1 in which the acid catalyst isp-toluenesulfonic acid.

5. A process as claimed in claim 1, in which the resulting tri-ether ofthe 1a,3,3-trihydroxy-5a-steroid is hydrolyzed under mild acidicconditions to obtain an ether of a 1u-hydroxy-3-keto-5a-steroid havingat the ring A the structure:

in which R is a lower hydrocarbon radical.

6. A process as claimed in claim 5 in which the hydrolysis is carriedout at about room temperature in the presence of oxalic acid.

7. A process for the preparation of ethers oflot-hydroxy-3-keto-5u-steroids having at the ring A the structure:

the structure:

with an alcohol of formula ROH and an orthoformate of formula H-C(OR) inwhich R is as hereinabove defined, under anhydrous conditions at atemperature below 60 C. in the presence of an acid catalyst andthereafter working the reaction mixture under aqieous acidic conditions.

8. A compound of formula:

in which R is a lower hydrocarbon radical, Y is selected from the groupconsisting of hydrogen, a ketonic oxygen and a B-hydroxy group, X isselected from the group consisting of hydrogen and fluorine, Z isselected from the group consisting of hydrogen and an acyl group derivedfrom a carboxylic acid containing up to 9 carbon atoms and R is selectedfrom the group consisting of hydrogen and lower alkyl, provided that Xis fluorine only when Y is fi-hydroxy.

10 9. la,3,3-trimethoxy-l7flacetoxy-5a-androstane. 10.1(1,3,3-triethoxy-17fl-acetoxy-5a-androstane. 11. A compound of formula:

in which R is a lower hydrocarbon radical, Y is selected from the groupconsisting of hydrogen, a ketonic oxygen and a fi-hydroxy group, X isselected from the group consisting of hydrogen and fluorine, T isselected from the group consisting of hydrogen, OL'CH3, fi-CH and a-OZand Z is selected from the group consistin of hydrogen and an acyl groupderived from a carboiiylic acid containing up to 9 carbon atoms,provided that X is fluorine only when'Y is fl-hydroxy.

12. 1a,3,3 trimethoxy 21 acetoxy 5a pregnanl7u-ol-11,20-dione.

13. 1a,3,3 trimethoxy 1613 methyl 5a pregnane- 1 1p, 17 (1,2l-triol-20-one.

14. 101,3,3 trimethoxy 16a methyl 5oz pregnancl1,B, 171:,21-triol-20-one.

15. la,3,3 trimethoxy 9a fluoro 5a pregnancl1B,16u,l7a,2l-tetrol-20-one.

16. la,3,3 trimethoxy 9a a fluoro l6a,2l-diacetoxy- 5a-pregnane-11,9,17a-diol-20-one.

17. 1u,3,3 trirnethoxy 17a acetoxy c pregnan- 20-one.

References Cited UNITED STATES PATENTS 2,904,564 9/1959 Tristram.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 260397.4, 397.5

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,475,467 October 28 1969 Rinaldo Gardi et al.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1 line 63, "lowe" should read low Column 2 line 21 "alyl" shouldread allyl line 37 "or" should res of Column 3, lines 50 to 60 in theformula on the right,

the "OH OZ" group in the 2l-p0sition should read CH OZ Column 4, line 66the I .R. spectrum values "1050 1025 9Z5 84( and 755 cmf should read1150, 1110, 1095, 925 and 845 cm.' respectively. Column 5, line 4, theI.R. spectrum value "1050" should read 1040 line 12 "Examplies" shouldread Examples Columns 5 and 6 TABLE I tri-ether correspondir to Example6, "ld,3,3trimethyoxy" should read la,3,3trimethc same table firstcolumn, the starting material of Example 7 "androsten-S-B-one" shouldread androsten3-one same table first column, starting material ofExample 11, cancel "one", secc occurrence. Columns 7 and 8, TABLE II,first column, starting material of Example 26, "pregne" should readpregnene Column 7, line 67 "-2-" should read -3 Column 9 line 23,"aqieous" should read aqueous Signed and sealed this 17th day ofNovember 1970.

(SEAL) Attest:

EDWARD M. FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

